Brivanib alaninate VEGFR inhibitor loop might also be related to our data on upregulated AKT.

loop might also be related to our data on upregulated AKT. Recently, a new generation of mTOR inhibitors has been developed. Dual PI3K/mTOR inhibitors, such as BEZ235, EX147 and PI 103, inhibit PI3 K and both small molecules Brivanib alaninate VEGFR inhibitor of mTORC1/2.36 Adenosine triphosphate competitive mTOR inhibitors that selectively inhibit TORC1/2 molecules also have been reported to be effective against Pht transformed leukemia cells and to be less immunosuppressive than PI3K/mTOR inhibitors.37 The effectiveness of a new generation of mTOR inhibitors should also be investigated in our future studies, in particular, the efficacy of these inhibitors against quiescent or leukemic stem cells using a humanized leukemic mouse model. However, it was suggested that dual PI3K/mTOR inhibitors may cause a greater degree of immune suppression by affecting normal cell functions.
14 Although we have examined the colony formation of CD34t human umbilical cord blood and it was suggested that everolimus did not severely interfere with hematopoietic colony formation, the effects of everolimus and the new generation mTOR inhibitors on normal cells and TG100-115 677297-51-7 immune functions must be investigated in future studies. Acquired mutation in the BCR ABL gene also causes primary and secondary treatment failure in Pht leukemia. Our data suggest that imatinib resistant cell lines with T315I mutation can be inhibited with everolimus with downregulation of the mTOR pathway. The in vivo effect of everolimus on T315I mutated Pht leukemic cells is also indicated.
Further study is needed to determine the effect of everolimus on T315I mutated leukemia, especially in combination with a T315I inhibitor such as AP24534.38 In conclusion, we have investigated the imatinib and everolimus combination effect against human Pht quiescent leukemic cells utilizing a mouse model. Everolimus can improve the treatment of resistant Pht leukemia. These mice also provide the opportunity to evaluate the effects of new therapeutic modalities on leukemic cells in different stages of cell cycle. Conflict of interest Hitoshi Kiyoi received research grants from Novartis Pharma, Kyowa Hakko Kirin Co. Ltd and Chugai Pharmaceutical Co. Ltd. Tomoki Naoe received research grants from Janssen Pharma, Novartis Pharma, Kyowa Hakko Kirin Co. Ltd and Chugai Pharmaceutical Co. Ltd. The other authors have no conflict of interest.
Acknowledgements We thank the staff of the Center for Research of Laboratory Animals and the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine for their technical support. We are grateful to the Novartis Institutes for Biomedical Research for providing imatinib and everolimus for these experiments. We also are indebted to Y Nomura, R Tanizaki, T Kawake and C Wakamatsu for their technical assistance. This work was supported by Grants in Aids from the National Institute of Biomedical Innovation and from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Chronic myeloid leukemia results from expression of the constitutive tyrosine kinase activity of the Bcr Abl oncoprotein. Imatinib, a tyrosine kinase inhibitor, is highly effective in the treatment of cml. However, some patients treated with imatinib will fail to respond, will respond suboptimally, or will relapse because of primary or acquired resistance or intolerance. Research activities focusing on the

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